Insulin is permissive for powerful glucose-generated signaling metabolites that initiate a program of gene expression that increases hepatic utilization and decreases glucose production. Diabetes mellitus interrupts the relationship between insulin and glucose signaling, and leads to disregulated hepatic metabolic gene expression; the liver essentially becomes trapped in the fasted state, unable to process abundant extracellular metabolic fuel. Despite the predominant role of glucose signaling in the coordinated regulation of metabolic genes, very few laboratories are working to unravel the mechanisms of glucose action. My laboratory is one of these, and here we take a new approach to dissect the mechanisms of glucose signaling and the phenotypic switch of the liver as it transits from the fasted to the fed state. The transcription factor c-Myc has potent control over the regulation of cellular glucose metabolism and is a candidate for coordinating changes in gene expression that occur at the end of a fast. Our recently published and preliminary data demonstrate that endogenous levels of c-Myc are required for glucose-regulated gene expression in hepatocytes, and that c-Myc binds to the promoters of glucose-responsive genes in a glucose-dependent manner. Together, these data provide evidence that c-Myc plays an active and direct role in the coordinated expression of metabolic genes by glucose metabolism. We hypothesize that c-Myc is necessary for glucose mediated gene transcription and normal glucose metabolism in hepatocytes, and that glucose modifies c-Myc activity. Specific Aim 1 will determine the alterations in gene expression patterns and the metabolic consequences of acutely reducing or increasing expression of c-Myc in hepatocytes. Specific Aim 2 will determine the mechanisms by which c-Myc regulates metabolic gene expression. The studies outlined in the present proposal will provide new insights into the mechanisms by which c-Myc coordinates glucose regulated gene expression and promotes the fasted-to-fed transition in the liver. The long-range goal of these studies is to understand the coordinating mechanisms of glucose-regulated gene expression so that interventions may be developed to circumvent impaired insulin signaling and improve glycemic control in diabetic patients. [unreadable] [unreadable]